title: Fluoxetine inhibits corticotropin-releasing factor (CRF)-induced behavioural responses in rats.
abstract: Corticotropin-releasing factor (CRF) is a potent neuromodulator of stress-related behaviour but the neural mechanisms underlying these effects are not clear. Studies were designed to test the hypothesis that CRF-induced behavioural arousal involves interactions with brainstem serotonergic systems. To examine interactions between CRF and serotonergic systems in the regulation of behaviour, CRF (1 microg, intracerebroventricular (i.c.v.)) or vehicle was infused in the presence or absence of the selective serotonin re-uptake inhibitor fluoxetine (0, 0.1, 1 or 10 mg/kg, intravenous (i.v.)). Fluoxetine was used at these doses because it is known to decrease serotonin cell firing rates while increasing extracellular serotonin concentrations in select forebrain regions. We then measured behavioural, neurochemical and endocrine responses. CRF increased locomotion and spontaneous non-ambulatory motor activity (SNAMA) in the home cages. Fluoxetine decreased tissue 5-hydroxyindoleacetic acid concentrations, a measure of serotonin metabolism, in specific limbic brain regions of CRF-treated rats (nucleus accumbens shell region, entorhinal cortex, central nucleus of the amygdala). Furthermore, fluoxetine inhibited CRF-induced SNAMA. CRF and fluoxetine independently increased plasma corticosterone concentrations, but the responses had distinct temporal profiles. Overall, these data are consistent with the hypothesis that CRF-induced facilitation of behavioural activity is dependent on brainstem serotonergic systems. Therefore, fluoxetine may attenuate or alleviate some behavioural responses to stress by interfering with CRF-induced responses.
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lowry
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hale
authors.forename: Andrea
authors.initials: A
authors.lastname: Plant
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Windle
authors.forename: Nola
authors.initials: N
authors.lastname: Shanks
authors.forename: Susan A
authors.initials: SA
authors.lastname: Wood
authors.forename: Colin D
authors.initials: CD
authors.lastname: Ingram
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Renner
authors.forename: Stafford L
authors.initials: SL
authors.lastname: Lightman
authors.forename: Cliff H
authors.initials: CH
authors.lastname: Summers
mesh_terms: D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000502:physiology*; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007276:Injections, Intraventricular; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism
chemical_list: D005473:Fluoxetine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone